The long-range goal of this project is to understand how the polymorphism of HLA class II D-region products influences immune response and susceptibility to autoimmune disease such as rheumatoid arthritis (RA) and insulin-dependent diabetes mellitus (IDDM). T cells recognize antigen in the context of HLA class II molecules and allelic differences in class III molecules and activate alloimmune T cells. In this project, we will use cloned T cells to define individual recognition sites on D-region products as a means for identifying structural variants that might play a role in immune response. These recognition sites also might be informative for the study of disease susceptibility. There are three components to our proposal. First, we will generate T cell clones that recognize the polymorphic sites on D-region molecules associated with the DR3 and DR4 family of haplotypes. These T cell defined epitopes will be localized to specific HLA-D loci and molecules, and eventually these recognition sites will be mapped on individual HLA-D alpha and beta chains. Second, we will determine which of these T cell defined epitopes might be associated with susceptibility to RA and IDDM. Analysis with pertinent T cell clones should yield definitive information about the role of class II immune response genes as risk factors in these diseases. Third, T cells activated in vivo will be cloned from RA patients to determine whether autoreactive T cells occur in blood or synovial tissues, whether they recognize tissue-specific antigens and whether they are specific for or restricted by any particular HLA-D determinants. These latter experiments may lead to the development of a model for understanding the nature of the immune response involved in the pathogenesis of RA.